The aim of this Program is to investigate mechanisms of kidney graft dysfunction using an experimental model of renal transplantation. Each project focuses on the role of elements, either constitutive to the kidney graft or produced within the graft during inflammation, which influence the alloimmune response. In Project #1 (Kidney Alloantigens in Graft Rejection, PI: T. Coffman), the role of kidney alloantigens in shaping rejection responses will be examined. Mechanisms of rejection of kidneys lacking particular MHC antigens will be examined. In addition, T cell receptor VBeta chain diversity used in response to a kidney allograft will be determined and the effects of alterations in donor alloantigen expression on the TCR repertoire will be defined. Project #2 (The Microenvironment in Alloimmunity, PI: J. Platt) will examine the effect of the microenvironment in determining the intensity and dimensions of the alloimmune response to a kidney graft. In particular, the role of endogenous renal cells and antigen presenting cells will be examined, focusing on glycosaminoglycans and lipid inflammatory mediators as intermediates in this process. Finally, attempts to modulate alloimmune responses will be undertaken using gene transfer techniques directed at factors in the renal microenvironment. In Project #3 (The Role of Leukotrienes in Immune Responses, PI: B. Koller), the role of leukotrienes in regulating inflammatory responses will be examined by constructing mice in which key enzymes involved in leukotriene synthesis will be abrogated through gene targeting. These mutant animals will provide novel and powerful tools for studying leukotriene metabolism and the role of leukotrienes in a variety of immune functions, focusing specifically on renal transplant injury. This program Project should continue to provide insight into the mechanisms of kidney transplant dysfunction with goal of providing new diagnostic and therapeutic approaches to problems in clinical transplantation.